Imaging

Renal cell carcinoma

What every physician needs to know:

Renal cell carcinoma (RCC) accounts for 3% of malignant tumors and is the seventh leading cause of cancer deaths in the USA. An estimated 63,000 new renal tumors were diagnosed in 2013 with over 13,000 deaths. It is most common in the seventh decade of life, and there is consistent male to female predominance (2:1).

There has been significant progress in the understanding and management of this RCC within the past 10 years, and emerging surgical and systemic therapy strategies have revolutionized the management of this disease.

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In localized disease, partial nephrectomy for small tumors and radical nephrectomy for larger tumors are now the gold standard. Currently, there is an emphasis on less invasive approaches with preservation of renal function.

Cytoreductive nephrectomy in patients with synchronous metastatic disease remains a standard before patients receive systemic treatment. The current approaches for management of patients with metastatic RCC (mRCC) utilize knowledge of histology, molecular abnormalities, clinical prognostic factors and the efficacy/toxicity of available agents.

The role of immunotherapy with cytokines remains controversial, and mainly limited to good prognosis patients. Development of immune checkpoint inhibitors represents a major advance in the application of immunotherapy, and multiple agents inhibiting cytotoxic T-lymphocyte antigen 4 (CTLA4), programmed death 1 (PD1), and PD ligand 1 (PDL1) are currently in clinical trials, and nivolumab, a PD1 antibody, has been approved for use. Development of therapies which target relevant biologic pathway elements also represent a principal treatment advance. Agents blocking angiogenic pathways – such as sunitinib, pazopanib, cabozantinib, sorafenib, and bevacizumab – the mammalian target of rapamycin (mTOR) inhibitors, everolimus and temsirolimus, and the checkpoint inhibitor nivolumab have demonstrated efficacy and offer new strategic options for patients with metastatic RCC.

Are you sure your patient has renal cell carcinoma? What should you expect to find?

Clinical presentation

Patients with RCC can present with either local or systemic symptoms; however, the most frequent presentation currently is incidental. This is secondary to the widespread use of abdominal imaging and the incidental discovery of a small renal mass.

Local signs and symptoms:

hematuria

flank pain

palpable abdominal mass

When present, these clinical features may carry negative prognostic implications. Systemic symptoms can be due to metastases or paraneoplastic phenomena such as:

hypercalcemia

unexplained fever

erythrocytosis

wasting syndromes

The diversity of paraneoplastic syndromes associated with RCC is remarkable, and historically RCC was often termed “The Internist’s Tumor.” Since ultrasonography and computed tomography (CT) imaging are associated with incidental detection of many asymptomatic renal tumors, RCC is also often referred to as “The Radiologist’s Tumor.”

Renal cell carcinoma subtypes

A major advance in understanding RCC is the realization that this disease is not a single entity but rather a collection of different tumor types, each derived from the various parts of the nephron and possessing distinct genetic characteristics, histologic features and – to some extent – clinical phenotype.

Clear cell renal cell carcinoma

The most common epithelial renal tumor is clear cell RCC (80 to 85%). The name reflects the tumor cell’s high cytoplasmic lipid content, which dissolves during histologic preparation to leave a clear area in the cytoplasm.

The Fuhrman grading system based on nuclear morphology is a significant prognostic factor in clear cell RCC.

Papillary renal cell carcinoma

Papillary RCC represents a smaller fraction of renal tumors (10 to 15%), and is further divided into type 1 and a more aggressive type 2 variety.

Other subtypes

Chromophobe, collecting duct, unclassified and medullary – the latter occurring almost exclusively in patients with sickle cell trait – are more rare subtypes.

Sarcomatoid differentiation

Sarcomatoid differentiation is a not a histologic subtype, but refers to a growth pattern which can be found in any subtype. Sarcomatoid tumors contain spindle cells, increased cellularity and atypical cell that indicate a potentially aggressive disease course.

Beware of other conditions that can mimic renal cell carcinoma:

The differential diagnosis of a renal mass lesion depends upon the lesion size and its radiographic characteristics. The majority of renal masses are currently detected as incidental findings (>50% of patients), and not all are malignant tumors.

Small (≤4cm), solid, enhancing masses should be considered suspicious for RCC. Enhancement with intravenous contrast correlates with malignant histology in about 80% of cases. These tumors are very heterogeneous, 20% are benign, and only about 20–25% exhibiting potentially aggressive kidney cancer at the time of diagnosis.

In view of their characteristic radiographic appearance and ease of removal, small renal masses are not routinely biopsied. In the past, it was assumed these lesions were malignant, and they were managed accordingly. Presently, the management of such small lesions is under study. Active surveillance is considered reasonable in patients with small lesions. Larger tumors (>3cm) and those with aggressive appearance, such as an infiltrative growth pattern, are more likely malignant, and should be approached accordingly.

In patients with large renal masses where removal is planned, biopsy likewise offers no advantages. In the setting of metastatic disease or locally advanced, inoperable lesions, biopsy of the renal mass is a viable diagnostic option.

Renal tumors, such as angiomyolipomas, can be differentiated from RCC utilizing radiographic means. Table I summarizes some of the typical radiologic features for the different RCC tumors.

Table I.

Type

Location/Size

Mass Characteristics

Enhancement

Other Features

Renal Cell Carcinoma(clear cell)

Mass lesion, peripheral location

Finding of small mass is increasingly common (incidental finding)

Over 80% demonstrate contrast enhancement on CT scans

Most common renal tumor Calcification less common than other subtypes

Papillary Carcinoma

Variable size

Multiple primary renal lesions may be seen

Less contrast enhancement

Differentiation from cyst may be difficult

Oncocytoma(benign)

Peripheral mass with central scar

Well circumscribed mass

Hypodense lesions

Spoke wheel pattern on angiography

Chromophope Carcinoma

Peripheral location

Typically large mass lesion

Weak homogenous enhancement

Calcification common > 30%

Angiomyolipoma

Slow growing, benign

Fat present in tumor typically

Minimal contrast enhancement

Retroperitoneal hemorrhage may be seen

Collecting duct/Medullary Carcinoma

Centrally located mass

Infiltrative mass lesion

Minimal contrast enhancement

Renal contour preserved, advanced stage common

XP 11 Translocation

Typically “small” tumors

Lymph node involvement common

Typically hypovascular tumors

Advanced stage common

Metastatic renal tumor

Small size

Typically bilateral and multiple

Contrast enhancement less than renal parencyma

Seen in patients with advanced metastatic malignancy

Which individuals are most at risk for developing renal cell carcinoma:

Gender

RCC is a male-predominant (2:1) cancer.

Age

RCC typically presents in the sixth or seventh decade of life. The median age at presentation is approximately 60 years.

Genetic factors

The majority of RCC tumors are sporadic, and only 2-3% of RCC cases are familial. In patients with bilateral renal tumors or who are young (<40 years old), a search for genetic causes of RCC should be considered. There are several autosomal dominant syndromes described, each with a distinct genetic basis and phenotype.

Von Hippel Lindau (VHL) Syndrome

Von Hippel Lindau (VHL) syndrome is the most common genetic syndrome associated with RCC. These patients are at risk for the development of tumors in a variety of organs, including the kidney. In RCC patients with a family history of retinal angioma, cerebellar or spinal hemangioblastoma, pancreatic neuroendocrine tumors, or pheochromocytomas, the presence of this syndrome should be suspected. In these cases, testing for germline mutations of the VHL gene should be considered.

A hereditary syndrome in which the VHL gene does not contain a mutation, but is associated with an increased risk of developing clear cell RCC, has also been described. This familial syndrome should be considered if more than one family member has been diagnosed with clear cell carcinoma, and germline mutations of the VHL gene are absent.

Hereditary papillary cancer syndromes

When patients are found to have multifocal papillary RCC tumors, hereditary papillary cancer syndromes should be considered. In patients with multifocal papillary type 1 cancers, hereditary papillary renal carcinoma HPRC) should be suspected. HPRC is caused by germline mutation of the MET gene.

These patients can develop bilateral kidney tumors and cysts, as well as cutaneous and uterine leiomyomas. HLRCC is characterized by a germline mutation of the Krebs cycle enzyme, fumarate hydratase. The renal tumors in HLRCC have pathologic features of type 2 papillary cancers, and demonstrate aggressive behavior. Lymph node metastases are common, and even when the primary tumor is small (<1 cm) metastatic disease may be found.

Birt-Hogg-Dube (BHD) syndrome

When multifocal chromophobe and oncocytic tumors are present, the Birt-Hogg-Dube (BHD) syndrome should be suspected. These patients also demonstrate benign cutaneous tumors, fibrofolliculomas, pulmonary cysts, and recurrent pneumothoraces. BHD is characterized by germline mutations of the BHD gene. In patients at risk, germline mutation testing for the BHD gene is recommended.

Familial renal oncocytoma (FRO)

In patients with multiple oncytomas of the kidneys, familial renal oncocytoma (FRO) should be suspected. These patients do not develop chromophobe tumors, do not have a mutation of the BHD gene, and do not develop the extra-renal manifestations of the BHD syndrome.

Tuberous sclerosis (TSC)

Patients with tuberous sclerosis (TSC) are at risk to develop bilateral renal tumors. These individuals may also have cutaneous lesions, central nervous system (CNS) hamartomas, and pulmonary cysts. Renal tumors in these patients are generally benign, and are most commonly angiomyolipomas. Reports of TSC patients with either clear cell, chromophobe, or papillary renal tumors have appeared.

Environmental factors

The major environmental risk factor associated with RCC development is either active or passive cigarette smoking, with a relative risk of approximately 2-3 fold. Other potential environmental etiologies such as acetaminophen/analgesic use, asbestos or trichloroethylene exposure have not been convincingly linked to RCC.

Clinical factors

Obesity (specifically body mass index [BMI]) is also a recognized risk factor. It has also been suggested hypertension is an RCC risk factor. Data suggests anti-hypertensive therapy such as diuretics is not independently associated with RCC development.

Finally, RCC is more common in patients with end-stage renal disease (ESRD), acquired renal cystic disease, and tuberous sclerosis. Autosomal Dominant Polycystic Kidney Disease (ADPKD) is not currently considered to be a risk factor for RCC; however, recent data suggests that the incidence of RCC in patients with ADPKD is higher than the rate for RCC in the general population, as well as that in patients with ESRD.

Most patients do not have an identifiable risk factor, and the pathogenic mechanisms underlying the established risk factors remain obscure.

What laboratory and imaging studies should you order to characterize this patient's tumor (i.e., stage, grade, CT/MRI vs PET/CT, cellular and molecular markers, immunophenotyping, etc.) How should you interpret the results and use them to establish prognosis and plan initial therapy?

Tumor stage

Tumor staging is an important component of current risk assessment techniques. Advanced tumor stages have been clearly correlated with poor prognosis, regardless of therapy. Using TNM staging guidelines, 5-year survival rates are as follows:

stage I: 95%

stage II: 88%

stage III: 59%

Stage IV: <20%

Several nomograms have been developed that utilize characteristics such as tumor size, stage, grade, pathologic findings and patient symptoms to predict disease-free and overall survival in patients with localized tumors.

Fuhrman grade

The Fuhrman nuclear grade of a renal tumor is another well established prognostic indicator. This scheme is based on nuclear size and shape, along with the prominence of nucleoli. 5-year survival rates are as follows:

grade I: 94%

grade II: 86%

grade III: 59%

grade IV: 51%

Histologic subtype

Patients with localized disease and non-clear cell histology have an improved prognosis compared to those having clear cell RCC. However, once metastases develop, non-clear cell histology is associated with a much poorer prognosis. Tumor size may also be a useful predictor for both local and locally advanced RCC.

Tumor size

A significant association between disease-free survival and tumor size has been reported. Additionally, patients with larger tumors are more likely to develop metastatic disease.

Clinical presentation

Survival is also associated with clinical presentation, especially if the patient is symptomatic at diagnosis. The median 5-year disease-free survival rates for initially symptomatic and asymptomatic patients are 57% and 83%, respectively.

Approach to staging

In patients with localized renal tumors, staging is accomplished primarily utilizing an abdominal/pelvic CT which will assess local invasiveness, lymph node involvement, and the presence of other metastases. Additional studies utilized for clinical staging include a chest CT, laboratory studies including complete blood counts, biochemical profiles (liver, renal, metabolic, LDH), and in selected patients CNS imaging and bone scans.

In patients with known or suspected metastatic RCC, staging plays a very important role in assessment of disease extent and prognosis. In contrast to individuals with localized renal tumors, end organ targets of metastatic disease are thoroughly investigated. Table II outlines the recommended studies.

Based on analyses from Memorial Sloan Kettering Cancer Center (MSKCC) and the Cleveland Clinic, the following factors have been associated with poor prognosis in stage IV disease:

Low Karnofsky performance status (<80%).

Low serum hemoglobin (

High corrected calcium (>10 mg/dl).

Elevated LDH (>1.5 x upper limit of normal).

Short disease-free interval (<1 year from diagnosis to start of systemic therapy).

Prognostic groups were defined as:

Favorable (no factors): median overall survival 28 months.

Intermediate (1-2 factors): median overall survival 13.6 months.

Poor (>=3 factors): median overall survival 4.6 months.

These risk criteria were then utilized in a series of phase II and III clinical trials for purposes of patient stratification. They can also be utilized to assist in guiding initial choice of therapy for patients with mRCC. Even though these criteria were developed in the cytokine era, they remain valuable prognostic tools in the current era of targeted therapy.

The MSKCC scheme was developed to assess untreated patients. In refractory patients, this scheme has been modified. In patients with prior therapy, three factors have been identified as associated with poor risk:

Low performance status

Anemia

High corrected serum calcium

Median overall survival according the number of risk factors:

0: 22 months

1: 11.9 months

>2: 5.4 months

This scheme has been utilized in several recent clinical trials for stratifying patients upon study entry. It is unclear if this approach is of value clinically, since analysis of data from the recent RECORD 1 trial did not demonstrate different efficacy patterns for the three prognostic categories.

In addition, neutrophils greater than normal and thrombocytosis were independent adverse prognostic factors.

Patients were again segregated into three categories:

Favorable (no adverse factors): median OS not reached; 2-year OS 75%.

Intermediate (1-2 factors): median OS 27 months.

Poor risk (>3 factors): median OS 8.8 months.

This model validated components of the MSKCC model, with the addition of platelet and neutrophil counts. It is under evaluation for patients receiving VEGF-targeted agents.

Staging

Table III. TNM staging for renal cell carcinoma.

What therapies should you initiate immediately i.e., emergently?

Immediate therapy may be required if a medical emergency related to metastatic RCC has developed. These are uncommon at the time of initial diagnosis, but the following list summarizes the potential varieties that may be encountered:

Neurologic

CNS metastases

Spinal cord compression

Osseous

Impending fracture and pain

Hypercalcemia

Bleeding

Gross hematuria secondary to primary tumor

Hemoptysis secondary to intra-bronchial lesion

Venous thromboembolic

IVC thrombus with Budd-Chiari Syndrome

Left atrial thrombus

Multiple pulmonary emboli

The majority of these require some form of emergent therapy. Treatment should be initiated rapidly, while a tissue diagnosis and staging studies are conducted. The type of therapy required is determined by the nature of the complication. Nephrectomy for locally advanced RCC may play a prominent role in patients presenting with IVC or left atrial thrombi. CNS metastases and spinal cord compression may require radiation therapy and/or surgery for optimal palliation.

The metabolic complication of hypercalcemia may be seen in RCC patients with extensive osseous metastases, but has become less common with the widespread use of bisphosphonates to decrease the skeletal complication rate in RCC patients.

What should the initial definitive therapy for the cancer be?

The treatment of patients with RCC can be considered from the perspective of the roles of surgery and systemic therapy. RCC is still predominantly a surgical disease for which radical surgery is justified and strongly indicated in specific situations. The role of systemic therapy has evolved within the past five years, and is increasingly important in patient management.

The application of these two modalities depends upon stage, histology, prognostic factors, and the patient’s co-morbid disease. Table IV summarizes therapeutic approaches potentially utilized in the various RCC stages.

Localized renal cell carcinoma

Small tumors (<4.0cm)

Patients with small renal masses are being seen with increased frequency. Treatment options have recently expanded, and have produced some controversies. Traditionally, these patients are treated aggressively, with radical nephrectomy. It is now clear that this approach may predispose patients to development of chronic kidney disease with attendant cardiovascular risks.

Nephron-sparing approaches such as partial nephrectomy, thermal ablation, and active surveillance have emerged as viable options. Nephron-sparing approaches are considered in patients with small renal masses, if tumor control is possible. Partial nephrectomy remains the reference standard for the management of small renal masses.

Active surveillance or observation is a reasonable approach for management of small localized renal tumors. It is a primary consideration for patients who have a decreased life expectancy and/or significant comorbidities making them high risk for surgery.

The thermal ablative procedures (cryoablation, radiofrequency ablation) are also options for high-risk patients who desire active therapy rather than observation. A tumor biopsy should be obtained prior to treatment to define histology. Post-treatment biopsy should also be considered.

Patients should be informed of the increased risk of local recurrence, the potential need for repeat ablation, or the possibility of difficult salvage surgery if tumor progression develops. Larger tumors, and those with an infiltrative appearance may be associated with an increased risk of recurrence compared to surgery.

Larger (>7.0 cm) and/or locally advanced tumors

A tumor over 7.0 cm has an increased potential of malignancy and invasiveness. In approximately 5 to 10% of renal tumors, tumor thrombus may extend into the venous system, often involving the ascending inferior vena cava, up to and including the right atrium. Generally, these tumors are managed by radical surgery.

The goal is total surgical excision, presuming the patient is a surgical candidate and vital structures are not compromised by surgery. Locally advanced renal tumors are managed with radical nephrectomy. Occasionally, en bloc resection of adjacent structures, isolation and temporary occlusion of vessels with thrombectomy, and cardiopulmonary bypass may be required. Despite the locally advanced nature of their tumors, over 40% of patients can be cured with such aggressive approaches.

The role of postoperative adjuvant systemic therapy is currently unknown, and of no proven value. Therapy in this setting with a variety of tyrosine kinase inhibitors is currently being studied in a series of clinical trials.

Metastatic renal cell carcinoma

Metastatic renal cell carcinoma with primary tumor in place

In the past, it was estimated that 25 to 30% of RCC patients presented with metastatic disease and their primary tumor in place. Recently, this presentation has become less common, perhaps related to the increased frequency of incidentally discovered renal masses.

Nephrectomy in patients with metastatic RCC (debulking or cytoreductive nephrectomy) is often part of an integrated management strategy. In the 1990s, two studies were conducted in which patients were randomized to either nephrectomy or no surgery, both followed by interferon alfa (IFN-a). In the combined analysis of these trials, the median survival was 13.6 months for the group treated with debulking nephrectomy followed by IFN-a compared to 7.8 months for IFN-a alone.

The mechanisms responsible for this beneficial effect are unknown. The cytoreductive paradigm remains the recommended approach in these patients, even though it has not yet been tested prospectively in patients who receive targeted therapy.

Presumably, the major effect seen is in patients with clear cell carcinoma. Cytoreductive nephrectomy in patients presenting with synchronous metastatic non-clear cell carcinoma has not been formally investigated. The type of systemic therapy recommended following cytoreductive nephrectomy is similar to that utilized in patients discussed in the subsequent paragraphs.

Limited metastatic renal cell carcinoma

Patients with limited metastatic disease should be considered for metastasectomy. These individuals represent a minority (2-3%) of cases, but long-term disease control occurs in selected patients. Favorable prognostic factors include a long disease-free interval between diagnosis and metastasis development. This reflects an indolent course and the possibility that a metastasis may be solitary.

Patients with favorable features and isolated pulmonary metastases may have a 30% five-year survival with metastasectomy. Surgical resection of solitary metastases should be an option in selected patients.

Metastatic renal cell carcinoma

Current therapeutic approaches for management of metastatic RCC utilize knowledge of histology, molecular abnormalities, clinical prognostic factors, knowledge of the natural history of RCC, and the efficacy and toxicity of the available agents.

Since December 2005, ten new agents or combinations have been approved in the US for the treatment of advanced RCC:

Two (temsirolimus and everolimus) target the mammalian target of rapamycin (mTOR)

One is a humanized monoclonal antibody (bevacizumab, administered in combination with INFa) which targets vascular endothelial growth factor (VEGF).

The immune checkpoint inhibitor nivolumab, a monoclonal antibody targeting programmed death 1 receptor (PD1) and preventing its activation by PD-L1 on activated T cells, was approved in late 2015.

The novel combination of Lenvatinib (TKI) and everolimus (mTOR inhibitor) was approved in May, 2016.

The multi-targeted TKI, carbozantinib, has been compared to everolimus in a phase 3 randomized trial, and results have demonstrated the superiority of carbozantinib. Approval by the FDA of this agent was granted in April, 2016. In May 2016, the combination regimen of Lenvatinib (a TKI) and everolimus was approved. Both of these treatments were approved for RCC patients who had received prior anti-angiogenic therapy. Previously, interferon-a (INF-a) and interleukin-2 (IL-2) were the mainstays of therapy.

Additionally, several unique categories such as sarcomatoid differentiation and rare histologic subtypes are included. The preferred treatment recommendations have been reviewed by numerous groups including the National Comprehensive Cancer Network (NCCN), European Society of Medical Oncology (ESMO), European Urological Association (EUA), and during recent American Society of Clinical Oncology (ASCO) meetings. The data from the recent RCC clinical trials performed have been utilized to help define therapy in the treatment naïve and refractory groups, in other settings, the information is from individual reviews, retrospective analyses, and clinical anecdotes.

Table V outlines the various patient groups and treatment subsets.

Table V.

Treatment Status

Clear Cell RCC

Non-clear Cell RCC

Treatment Naive

Favorable Risk

No Groups Defined

Intermediate Risk

Poor Risk

Treatment Refractory

Cytokine Refractory

No Groups Defined

TKI Refractory – duration previous therapy

mTOR Inhibitor Refractory

Co-morbid Conditions

Recent Cardiovascular Event

Recent Cardiovascular Event

Impaired Renal Function

Impaired Renal Function

Impaired Hepatic Function

Impaired Hepatic Function

Unique Categories

Sarcomatoid Differentiation

Sarcomatoid Differentiation

CNS metastases

CNS metastases

Osseous Metastases

Xp11.2 Translocation

Elderly Patients

Collecting duct, medullary RCC

Metastatic clear cell carcinoma

The histologic diagnosis of clear cell carcinoma is important to assist in determining therapy. If there is uncertainty, the likelihood exists the underlying histologic pattern represents clear cell carcinoma, and therapy can be administered for this presumed diagnosis.

Treatment naïve, metastatic clear cell carcinoma

These individuals have not received previous systemic therapy. Most individuals will fall into this category.

Treatment naïve, favorable risk metastatic clear cell carcinoma

Patients in this category should have no poor risk factors (10 to 20% of patients). They generally have low volume metastatic disease, predominantly pulmonary metastases, are asymptomatic, and may have long disease-free intervals.

The therapy recommended in this group would include:

a TKI such as sunitinib or pazopanib,

or the combination of bevacizumab plus IFN-a.

All of these options are associated with clinical toxicity; therefore, risk-benefit assessment may be helpful when estimating the potential utility of starting treatment. There are patients in this category where therapy can be delayed, the rate of disease progression observed, and therapy initiated at a later time. Recently, the COMPARZ (phase 3) and PISCES (phase 2) trials have compared pazopanib and sunitinib as first line therapeutic options. Pazopanib was found to be non-inferior to sunitinib, but importantly patient tolerance and preference favoured pazapanib. Everolimus has been shown to be inferior to TK1 therapy in the first line (RECORD-3 trial).

No published criteria are available that define this group; however, it probably includes the patient with low-volume disease, small but stable lung metastases, and a long disease-free interval. Not all patients with newly diagnosed metastatic RCC should receive immediate systemic therapy. Active surveillance, as in the case of small renal masses is a viable option.

An alternate therapeutic option in this category is cytokine therapy with high dose IL-2. This approach requires hospitalization, is associated with toxicity from the capillary leak syndrome, and a low rate of treatment associated mortality. It is generally utilized only in centers with significant expertise in administering high dose IL-2, and in patients who can tolerate this type of aggressive treatment.

Treatment naïve, intermediate risk metastatic clear cell carcinoma

This group contains the largest number of patients (60 to 70%). They are minimally symptomatic, most have had a prior nephrectomy, and have few, if any, laboratory abnormalities.

Therapy for this group should consist of:

A TKI, or

Combined bevacizumab and IFN-a.

Selection of the specific agent or regimen will depend on the presumed risk benefit of each approach in patients; however, all of the options are acceptable. No comparative trials have been published that define differences or similarities between these treatments.

Occasionally, patients in this group will have disease compromising vital organ function, e.g. mediastinal lymph nodes producing respiratory compromise, hematuria secondary to a primary tumor. In this setting, rapid tumor response is desirable. The agent with the highest likelihood of response may be the best alternative.

As with the favorable group, high dose IL-2 therapy is an option to be discussed with these patients dependent upon their age and cardiovascular status. The issues discussed in the favorable group are applicable in these patients.

Treatment naïve, poor risk metastatic clear cell carcinoma

This group of patients has the largest tumor burden, are symptomatic, may have their primary tumors in place (10 to 15% of patients).

Treatment generally consists of:

The mTOR inhibitor temsirolimus.

This is the only treatment that has been examined in a phase 3 trial in these patients. This agent was well tolerated by poor-risk patients, without excessive toxicity noted. In view of these level 1 data, therapy with weekly intravenous temsirolimus is recommended for poor-risk patients. Use of sunitinib in this group is poorly defined; however, a phase 3 trial comparing sunitinib to IFN-a suggested selected poor risk patients may benefit. The role of other first-line treatment options such as pazopanib or bevacizumab plus IFN-a remains poorly defined.

Treatment refractory, metastatic clear cell carcinoma

The majority of patients receiving a targeted agent will have partial responses or stable disease, and will ultimately progress. The mechanisms responsible for the development of resistance are unclear, and therapeutic decisions require knowledge of previous therapy, as well as response or clinical benefit related to front-line treatment. Therapy for refractory patients is best defined by considering the type of initial treatment, and whether the resistance is acquired or intrinsic.

Cytokine refractory, metastatic clear cell carcinoma

Use of cytokines as initial therapy is currently limited, but some of the earlier clinical trials have defined treatment of this patient population. The TKIs sorafenib, sunitinib, pazopanib, or axitinib can be utilized. The data for sorafenib and axitinib are from randomized trials. Axitinib proved superior in prolonging progression-free survival (PFS), and is generally considered as the first choice for these patients. Sunitinib and pazopanib represent alternatives. Response rates to sunitinib or pazopanib are 30 to 40%, and PFS between 7 and 8 months. The recent data for axitinib suggest a similar response rate and PFS.

The available data in cytokine refractory patients suggest initial therapy with the TKI axitinib should be considered based on the trial size and design. Alternatively, either sorafenib, sunitinib, or pazopanib can be utilized based on available data.

TKI Refractory, metastatic clear cell carcinoma

Although targeted therapies have become the new cornerstone of systemic RCC therapy, eventual treatment-emergent resistance has become a major impediment to long-term success with these new agents.

To address this issue the mTOR inhibitor everolimus was tested in patients progressing after sorafenib and/or sunitinib. Patients receiving everolimus compared to placebo showed prolongation of PFS with acceptable side effects. These data supported the use of this agent as second-line therapy in patients failing initial treatment with a TKI. One rationale for this sequence is the use of an agent with an alternate mechanism of action.

Subsequent trials of other TKIs such as axitinib, cabozantinib (a multikinase inhibitor with activity against VEGF, MET, and AXL), Lenvatinib and everolimus, and the immune checkpoint inhibitor nivolumab (discussed below) have used everolimus as a benchmark, and all demonstrated superiority. As a consequence, single-agent everolimus is no longer commonly used as a second-line therapy. Lenvatinib, another anti-VEFG TKI given with everolimus, has been shown to prolong progression-free survival over everolimus alone and the combination is approved for use after progression on a prior anti-angiogenic therapy.

The standard of care in TKI refractory patients continues to evolve as new data become available. Based on phase 3 data demonstrating their superiority to everolimus, nivolumab and cabozantinib are the current preferred agents following progression on a prior TKI, although axitinib or the combination of everolimus and lenvatinib are supported by similar data and are reasonable options. The optimal agent or sequence of agents is not yet established.

Another approach in these refractory patients is re-challenge with the same agent, or another TKI. The concept of sequential utilization of several TKI’s has been proposed. Evidence demonstrating efficacy comes from phase 2 trials and a recent phase 3 trial comparing axitinib to sorafenib. In the setting of sunitinib failure, second responses to the same drug have been described.

A phase 3 study (Checkmate 025) comparing everolimus with nivolumab after progression on one or two prior anti-angiogenic therapies demonstrated an improvement in overall survival (25 vs. 19.6 months), and objective response rate (25% vs. 5%) for patients receiving nivolumab. This was only the second trial to demonstrate an improvement in overall survival among the newer targeted agents, the first being temsirolimus.

Unlike with other malignancies (e.g., lung, melanoma) programmed death ligand 1 (PDL1) expression on tumor cells was not a reliable predictor of response, and in fact patients with <1% expression had slightly better overall survival on nivolumab than patients with >1% expression. It has previously been reported that increased PDL1 expression is a poor prognostic marker in clear cell carcinoma.

The most common adverse events of immune checkpoint inhibitors are fatigue, low-grade nausea, and anorexia. No standard premedication is given.

Autoimmune toxicities affecting specific organs occur in a minority of patients. Clinical syndromes include pneumonitis, thyroiditis, colitis, hepatitis, dermatitis, nephritis, hypophysitis, endophthalmitis, and others have been observed. Their management is addressed under the “What if scenarios” below. As a consequence of these toxicities, immune checkpoint inhibitors should be avoided in patients with pre-existing autoimmune disease or patients requiring chronic high-dose steroids.

mTOR inhibitor refractory, clear cell carcinoma

The group of patients who fail first-line therapy with an agent such as temsirolimus generally represent poor-risk patients who had initially responded or had disease stability. The numbers of patients in this group represent approximately 35% of those treated in first-line. Data to assist treatment decisions in this group is lacking currently; however, a second line TKI is a reasonable alternative. For dosing, schedule, and toxicity of targeted agents, see Table VI.

Table VI.

Dose, schedule and toxicity

Co-morbid conditions, metastatic clear cell carcinoma:

Recent cardiovascular event

Cardiovascular toxicity in the form of hypertension appears to represent a class effect of the VEGF/VEGF receptor (VEGFR) inhibitors. Treatment-induced hypertension also appears to correlate with clinical outcomes in RCC. This has been shown retrospectively for therapy utilizing sunitinib, axitinib, or bevacizumab.

These analyses have utilized several definitions of hypertension such as grade of toxicity or specific systolic and/or diastolic blood pressure levels. Correlations with objective response, PFS, and overall survival have been consistently found in patients who develop treatment-induced hypertension. This finding is being investigated prospectively, and the mechanisms underlying this phenomenon are unclear. Pre-existing hypertension should not therefore be considered a contraindication to the use of TKI’s or bevacizumab.

Cardiac dysfunction in the form of left ventricular dysfunction has been reported with the TKI’s sunitinib and sorefenib (>10%). A history of congestive heart failure or a decreased LVEF is a relative contraindication to the use of these agents. Studies with pazopanib suggest cardiac dysfunction is not seen with this TKI. In view of this, pazopanib appears to represent an alternative for this patient group, as well as individuals with a recent (<6 months) acute cardiovascular episode such as a myocardial infarction.

Impaired renal function

Abnormal renal function is frequently noted in patients with advanced RCC. The safety and efficacy of VEGF-targeted agents in patients with renal insufficiency is therefore relevant. Pharmacokinetic studies of various TKIs have demonstrated renal elimination is a minor component of drug metabolism. Hepatic metabolism is the major pathway. Therefore, it was assumed that the TKIs can be safely given to patients with renal insufficiency.

Retrospective reviews have shown that sunitinib and sorafenib can be administered to patients with impaired renal function. Monitoring of renal function is recommended, since TKI administration may produce serum creatinine elevations. Patients with worsening renal function may require dose modifications. Recent data from the CALGB has suggested that sorafenib dose can be maintained with a creatinine clearance above 40 mL/min, but below this level, dose reductions are required.

Patients with metastatic RCC on hemodialysis represent a distinct population. Information is largely anecdotal in this group, and two recent retrospective reports suggest administration of sunitinib is possible with acceptable toxicity. Dose levels have varied, with patients receiving either 50, 37.5 or 25 mg PO daily utilizing the 4 weeks on/2 weeks off schedule.

Impaired hepatic function

Hepatotoxicity is a recognized class toxicity of the TKIs, irrespective of the targets inhibited. Metabolism of these agents is primarily by the liver, and administration to patients with impaired liver function has not been studied adequately. However, some information is available in this patient group.

Preliminary data from a dose escalation study with pazopanib demonstrated that drug clearance is decreased by 50% in patients with moderate hepatic impairment when compared to individuals with normal hepatic function. The maximum tolerated dose in patients with moderate impairment of hepatic function is 200 mg PO daily. No data is available for patients with severe hepatic impairment, and pazopanib is not recommended in this setting.

Hepatic toxicity with sunitinib has also been reported. Comparison of data from the phase 3 pivotal trials suggests grade 3 toxicity may be more common with pazopanib. The safety of sunitinib in patients with hepatic enzyme elevation over 2.5 times normal or, if due to liver metastases, above 5.0 times normal, has not been established, and it is not recommended in these individuals

The use of sorafenib in patients with hepatic impairment has been more adequately characterized. Pharmacokinetic studies of sorafenib have been conducted in patients with hepatocellular carcinoma. Hepatic impairment may reduce plasma concentrations of sorafenib, and comparison suggests sorafenib levels may be lower in these patients than in non-hepatocellular patients (without hepatic impairment).

The area under the time-concentration curve (AUC) of sorafenib is similar in patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment who have hepatomas. No dose adjustment is necessary in patients with Child-Pugh A and B hepatic impairment. Sorafenib has not been studied in patients with severe (Child-Pugh C) hepatic impairment.

The mTOR inhibitors everolimus and temsirolimus require dose modification in patients with hepatic impairment. For temsirolimus, the recommended starting dose in patients with mild hepatic impairment (bilirubin > 1.0 to 1.5 x normal, or AST > normal with normal bilirubin) is 15 mg IV weekly. Similarly, a dose reduction of everolimus to 5mg daily is recommended in patients with Child-Pugh class B. These agents have not been adequately studied in patients with severe hepatic impairment.

Finally, bevacizumab can be utilized in RCC patients with impaired hepatic function. Although no formal evaluation in this patient population is available, hepatic toxicity is not a prominent feature of this agent.

Because of the limited information available for RCC patients with hepatic impairment, liver function tests (ALT, AST, bilirubin) should be monitored before initiation of treatment, during each treatment cycle, and as clinically indicated.

Unique patient categories, clear cell carcinoma

Sarcomatoid differentiation, metastatic clear cell carcinoma

Sarcomatoid differentiation in RCC occurs when the malignant cells acquire a higher grade, have a spindle cell appearance, and evidence of epithelial and mesenchymal differentiation. The reported incidence of RCC sarcomatoid differentiation is estimated between 1% and 23% of cases.

Patients whose pathology report notes “sarcomatoid change” appear to have a worse prognosis with a median survival less than one year. There is no uniform definition of sarcomatoid RCC such as the percentage of sarcomatoid differentiation required for the diagnosis. Chemotherapy with doxorubicin-containing combinations has been evaluated in these patients, and occasional tumor shrinkage is seen.

Targeted agents have also been evaluated in this patient group. In these reports, tumor shrinkage has been reported, but the data are retrospective for the most part. Several important points are noted:

The prognosis of patients with sarcomatoid tumors is poor.

Pathologic criteria for a diagnosis are variable.

The underlying histologic pattern may be crucial for determining therapy.

Currently, the data does not support one particular option, however, responses to sunitinib in clear cell carcinoma with sarcomatoid elements have been reported.

Chemotherapy with agents such as fluorouracil and/or cisplatin has also been reported to produce tumor regressions in selected patients, but the overall results with this group of agents is poorly characterized.

CNS metastases, metastatic clear cell carcinoma

Patients with brain metastases are generally not eligible for clinical trials, and therefore prospective data are limited. Therapy for patients with newly diagnosed CNS metastases will generally require radiation (whole brain and/or stereotactic) or surgical removal, dependent upon the location, size and number of lesions.

Previously, patients with CNS metastases secondary to RCC received only supportive therapy, but aggressive approaches in selected patients will often permit additional systemic therapy to be considered. The effects of systemic therapy in this patient population are not entirely clear. A retrospective subgroup analysis of patients receiving sorafenib suggested a decreased incidence of CNS metastases in patients treated with sorafenib compared to placebo (3% vs. 12%, P<0.05). This data has not been confirmed.

In the sunitinib expanded access study, 7% of patients (n=321) had treated brain metastases and received open label sunitinib. The median PFS of this group was 5.6 months, and median survival was 9.2 months. No differences in toxicity were seen when patients with CNS metastases and the overall population were compared.

The overall incidence of treatment-related adverse events was 92%, regardless whether CNS metastases were present or not. These results suggest that it is possible to utilize agents such as sunitinib in RCC patients with treated CNS metastases. Toxicity is acceptable, and control of systemic disease may be seen. The best systemic therapy for patients with CNS metastases remains unclear, but if considered, a TKI is a reasonable option.

Osseous metastases, clear cell carcinoma

Bone is a common site of metastasis in RCC patients, with a frequency of solitary or multiple osseous metastases ranging from 24% to 51%. Complications associated with bone metastases include decreased performance status, pain, pathologic fracture, spinal cord compression and hypercalcemia. Management of this patient group depends upon patient status, presence of co-morbid factors, and whether the osseous metastases are solitary or multiple sites are involved.

Supportive measures include:

radiation therapy

surgical removal and/or fixation

pain control

bisphosphonates or denosumab

Patients should receive supportive measures as previously described, the indicated systemic therapy for their disease, and treatment with a bisphosphonate such as zoledronic acid based on the results of a randomized placebo controlled trial (zoledronic acid versus placebo) in solid tumor patients with bone metastases.

RCC patients receiving zoledronic acid have reduced numbers of skeletal related events (SREs), delayed the time to the first SRE, and interestingly prolonged time to disease progression versus a placebo. Of interest are several reports suggesting a rapid improvement in metastatic bone lesions and patient symptoms after receiving zoledronic acid in combination with sunitinib.

Although there are no trials of bisphosphonates specifically in an RCC population, the available data suggests therapy with zoledronic acid and a TKI such as sunitinib has acceptable toxicity, and use of bisphosphonates delays the complications of bone metastases.

Recently, denosumab, a monoclonal antibody that binds and neutralizes receptor activator of nuclear factor kappa-B ligand (RANKL) was investigated in patients with solid tumors. A phase 3 trial comparing the effects of denosumab to zoledronic acid was conducted. Patients with RCC and osseous metastases were eligible; however, the report does not provide subset data on this population of patients. The results demonstrated the non-inferiority of denosumab in delaying skeletal complications. It is likely this agent has effects in RCC patients with bone metastases equivalent to zoledronic acid, but data are not yet available to confirm this.

Elderly patients, clear cell carcinoma

It has been suggested that older individuals may not benefit from treatment with the currently available targeted agents, and will develop an increased frequency of adverse events. Despite these concerns, age has not emerged as a poor-risk factor in recent analyses of prognostic factors. These issues have been examined in several of the recently reported trials with sunitinib, sorafenib, and bevacizumab + IFN.

Overall, data from these clinical trials and meta-analyses demonstrate elderly patients aged greater than 65 or 70 years can be treated in a fashion similar to their younger counterparts. They appear to have similar degrees of benefit, and tolerate TKI or bevacizumab plus IFN-a therapy in a manner similar to younger patients.

Metastatic non-clear cell carcinoma

RCC is a heterogeneous disease, comprised of several different histological types with distinct genetic alterations, varying clinical course, and variable responsiveness to systemic therapy.

The main histopathological RCC subtypes based on tumor morphology, immunohistochemistry, cytogenetics and molecular studies include:

clear cell carcinoma (60-70%)

papillary (7-14%)

chromophobe (6-11%)

collecting duct carcinoma (0.3%)

Xp11 translocation carcinomas (<1%)

renal cell carcinoma unclassifiable (4-5%).

In earlier studies, RCC was considered a single disease classification. Currently these subtypes are categorized as either clear cell or collectively non-clear cell. Clinical studies have suggested chromophobe and papillary RCC have a better prognosis following nephrectomy for localized disease compared to clear cell RCC. The reverse appears true for patients with metastatic disease.

A recent retrospective analysis demonstrated metastatic non-clear cell RCC is resistant to systemic therapy and is associated with poor survival. It also was noted that patients with chromophobe RCC may have longer survival than those with papillary RCC. The treatment of patients with metastatic non-clear cell carcinoma remains an area that is poorly defined. Clinical trials for these tumors have been limited, and the available data is largely retrospective and/or analysis of patient subsets.

The subset analysis noted an overall survival improvement for patients treated with temsirolimus versus IFN-a (11.6 vs 4.3 months). Based on this exploratory analysis, temsirolimus appears to be efficacious in patients regardless of the underlying tumor histology, and importantly may be a useful drug for the treatment of patients with non-clear cell histology.

Retrospective analyses of patients with non-clear cell RCC receiving TKI’s suggest sunitinib may have a low level of activity, but its overall efficacy remains unclear.

Treatment refractory, non-clear cell carcinoma

Unlike clear cell carcinoma, minimal information is available on the therapy of patients failing initial therapy. Presumably, an agent such as temsirolimus may be utilized as front-line treatment. At disease progression, it is likely a TKI may be utilized. There is no standard of care for this patient group. Patient functional status, co-morbid factors, and type of initial treatment will influence the choice for second-line therapy.

Co-morbid conditions, non-clear cell carcinoma

As in the patient with metastatic clear cell carcinoma, the various co-morbid conditions may influence therapy. The reader is referred to that section for a discussion of cardiovascular, renal, and hepatic factors that may modify or influence treatment.

Unique categories, non-clear cell carcinoma

Sarcomatoid differentiation, metastatic non-clear cell carcinoma

The influence of sarcomatoid elements in the various non-clear cell histologic groups on treatment outcomes for patients with metastatic disease is poorly defined. The role of chemotherapy versus the targeted agents such as the TKIs has not been adequately defined. Metastatic sarcomatoid RCC is associated with a poor response to systemic therapy. Studies to characterize the underlying tumor biology, to assess outcome to targeted agents, and to develop novel treatment strategies are needed.

CNS metastases, metastatic non-clear cell carcinoma

Data on frequency of CNS metastases in patients with the various non-clear cell histologies are not available. Therapy for these patients is similar to that described for clear cell carcinoma.

Xp11.2 translocation, metastatic non-clear cell carcinoma

RCC associated with Xp11.2 translocations (TFE3 gene fusions) are rare tumors predominantly in the pediatric age group; however, a small number of adult Xp11.2 translocation RCC cases have been described.

Histologically, this tumor can resemble either the clear cell or papillary carcinoma, and may contain elements of both. Given the degree to which these tumors overlap morphologically with clear cell and/or papillary RCC, many adult Xp11.2 translocation RCC may be misclassified. Optimal therapy is not defined for this patient group, but recognition is important since this type of tumor may not benefit from currently available targeted agents, although prolonged responses to a TKI such as sunitinib have been reported.

Collecting duct, medullary carcinoma

Collecting duct carcinoma (CDC) also referred to as “Bellini duct carcinoma,” is an uncommon, aggressive form of renal cell carcinoma, accounting for less than 2% of kidney cancers. CDC arises from the epithelium of the distal collecting system in the renal medullary pyramids. Prospective reports suggest chemotherapy may be useful, and data with TKIs such as sunitinib suggest no benefit. Current recommendations are to treat this histologic variant with chemotherapy utilizing a platinum based regimen.

Renal medullary carcinoma is also a rare tumor that is most common in young black men with sickle cell disease or trait. This entity is often confused with CDC or poorly differentiated transitional cell carcinoma. In the majority of experiences reported, this rare subtype is characterized as a highly aggressive disease. Recent reports suggest chemotherapy has anti-tumor activity in this variant.

Regimens utilized for the treatment of urothelial carcinoma include:

MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) or

Combination of cisplatin, paclitaxel, and gemcitabine.

Additional studies are needed to define the overall activity of platinum based chemotherapy in medullary RCC, but the anecdotal data available suggest this non-clear variant should be approached as a urothelial neoplasm.

What other therapies are helpful for reducing complications?

Supportive therapies that may be of value in the management of patients with metastatic RCC include those utilized to decrease the complications of osseous metastases:

Bisphosphonates: zoledronic acid

RANK ligand inhibitor: denosumab

What should you tell the patient and the family about prognosis?

Since treatment of metastatic RCC rarely produces complete responses, and cure is unlikely, current therapy is focused on control of disease progression. The median overall survival of these patients was in the range of 14 to 16 months during the cytokine era, and recently, median survivals of 23 to 26 months have been reported with various targeted agents.

The prognosis for patients with advanced metastatic disease can be estimated by utilizing the MSKCC criteria. They can be classified as having favorable, intermediate, or poor-risk disease, with median survivals of 28.0, 13.6 and 4.6 months. This data is from the cytokine era; recent reports indicate that with utilization of the current treatment paradigm, median survivals of 20.7 and 5.3 months in the intermediate and poor-risk groups respectively. In favorable-risk patients, median survival is now approaching 3 years.

The goal of therapy in metastatic RCC patients is to maximize therapeutic benefit, delay the development of a disease burden that becomes life threatening, and maximize a patient’s quality of life and convenience. This translates into selection of therapy with the optimal risk/benefit ratio for an individual patient. Unfortunately, only limited clinical criteria are available that predict efficacy, and ultimately multiple sequential treatments with available agents is utilized.

What if scenarios.

Recognition of histologic RCC subtypes is a frequent issue, and as pathologists become more familiar with current classification schemes, this will be less of an issue. Major issues in the field currently relate to the following questions:

1) What is the best therapy or standard of care in treatment naïve mRCC?

This will require comparative trials, several of which are underway. The phase 3 COMPARZ trial in which pazopanib was compared to sunitinib in this patient population has recently been reported. The study endpoints included PFS and survival, and utilized a non-inferiority design. Pazopanib was found not inferior to sunitinib. Additional phase 3 studies comparing various immune checkpoint inhibitors such as nivolumab + ipilumumab, TKI’s plus a checkpoint inhibitor (Lenvatinib + pembrolizumab, axitinib + pembrolizumab), Lenvatinib + everolimus, or bevacizumab + atezolizumab with sunitinib are underway. These will provide important information on the optimal therapy for untreated mRCC patients.

2) Is the use of the MSKCC scheme mandatory?

In the absence of biomarkers, this classification should be utilized to assist with treatment decisions. The IMDC classification represents an alternative approach, and can be employed.

3) What is the definition of refractory?

No pre-specified criteria are available, except as listed when utilizing RECIST criteria. In some patients, RECIST disease progression may be documented, but the patient is asymptomatic or minimally symptomatic. In this setting, continuation of current therapy is justified, until definitive evidence of new sites of disease is found, especially in patients with small volume metastases.

4) How should the adverse events associated with targeted therapy be managed?

This will vary with the agent and the adverse event type. A complete discussion of toxicity management for each agent is beyond the scope of this review, but several more common class effects are relevant to discuss:

a) Dose and schedule:

Lower doses may be employed if there are significant concerns about potential side effects; however, the results reported in the various phase 3 pivotal studies utilized a standard dose and schedule. In the case of sunitinib, a significant relationship between sunitinib exposure and efficacy/toxicity has been identified.

Patients with the highest exposure not only displayed a higher probability of a response and tumor shrinkage, but also longer time to progression and, most importantly, longer overall survival. This emphasizes the importance of maintaining patients at 50 mg dose of sunitinib and striving to avoid any unnecessary dose reductions during treatment.

Continuous dosing versus the intermittent schedule have been compared in a phase 2 randomized trial. No differences in adverse events were found, and the traditional intermittent schedule appeared superior.

Recently, use of sunitinib in alternate schedules has been studied. Two weeks of therapy followed by one week of rest has been suggested to be better tolerated than the traditional “4/2 schedule.” The “2/1schedule,” however, has not been compared directly to the original sunitinib schedule.

b) How should patient fatigue related to TKI therapy be managed?

Potential alternative causes for fatigue such as underlying dehydration, hypothyroidism, hypercalcemia, anemia or depression should be excluded. All patients should have thyroid function tests prior to and during TKI treatment (every 8 to 12 weeks) and be treated according to standard medical practice.

Thyroid hormone replacement is recommended in mRCC patients with overt hypothyroidism (defined as an elevated serum thyroid-stimulating hormone (TSH) level and a low T4 level) and possible hypothyroidism-related symptoms. Blood transfusions may be used at the discretion of the treating physician to correct anemia.

Depression, a frequent finding in metastatic cancer patients, is known to impact upon the severity of fatigue. Fatigue improves in some patients who have received antidepressants. Finally, patient education about fatigue and its occurrence is very important. On occasion drug holidays may be helpful, and if severe fatigue is a recurrent problem, dose reduction may be appropriate.

Currently, there are no evidence-based interventions to treat fatigue, and therefore when it interferes with quality of life, management by changes in dose would be appropriate.

c) How can the hand-foot syndrome be managed?

The frequency of this cutaneous complication varies dependent upon the TKI utilized. The lowest frequency is seen with pazopanib, and the highest with sorafenib. Hand–foot changes may present as painful symmetrical erythematous areas on the palms and soles. Patients may experience paraesthesias, tingling or numbness.

Desquamation can occur in severe cases. Painful hyperkeratotic areas in pressure regions surrounded by rings of erythema as well as bullous lesions and/or blisters may be noted. These are seen in areas of pressure, and pre-existing hyperkeratotic areas seem predisposed to development of these changes. When functional consequences develop, patients may refuse to continue therapy.

Palliative interventions include:

moisturizers

foot and hand care products (e.g. gel pad inserts, cotton gloves)

medication for pain management

instructing patients to decrease pressure on the areas affected, by staying off their feet if possible and avoiding pressure on their hands.

Treatment for grade 2 hand-foot syndrome usually involves these measures, as well as dose interruptions, and if necessary dose reductions. Dose interruptions for 5 to 7 days are generally sufficient to permit resolution of most severe skin changes. Anecdotal reports suggest steroid creams can be helpful, but well designed prospective studies are lacking. This complication is not an inflammatory response, but steroid creams may prevent secondary inflammatory changes.

When patients with hand-foot changes does not respond to dose interruption or reduction, other diagnoses should be considered such as fungal infection, allergic contact dermatitis, and irritant dermatitis. At this time referral to a dermatologic consultant would be appropriate. Finally, recent analysis of the sunitinib phase 3 trials suggests the development of hand-foot syndrome may correlate with efficacy.

d) How should diarrhea be managed?

Diarrhea occurs frequently, and over 50% of patients may experience this toxicity. Grade 3 and 4 diarrhea is uncommon. Some degree of diarrhea often remains when other common side effects have been controlled with dose/schedule changes.

In contrast to chemotherapy-induced diarrhea, which is usually continuous, TKI-induced diarrhea may be irregular. Dose reductions are rarely necessary for grade 1 and 2 diarrhea, which can be managed by oral anti-diarrheal agents as needed, such as loperamide. Treatment should be interrupted for grade 3 diarrhea until it has decreased to grade 1 or has returned to baseline. Patients should temporarily discontinue use of stool softeners and fiber supplements.

e) How should the hematologic toxicity secondary to the TKIs be managed?

Severe hematologic toxicity is infrequent in patients receiving either pazopanib or sorafenib, and most common in sunitinib-treated patients. Only 5 to 8% of sunitinib-treated patients develop grade 3/4 neutropenia or thrombocytopenia and few cases of neutropenic fever have been reported.

Blood counts usually recover quickly within the 2-week treatment break. Due to the usually rapid recovery of blood counts during the 2-week treatment break, hematologic growth factors are not routinely recommended.

Dose modification for grade 4 neutropenia or grade 3 thrombocytopenia may be required. Severe anemia usually does not require dose modification. Of interest are the macrocytic indices that frequently develop in sunitinib treated patients. These are related to therapy, and do not have an underlying nutritional cause. Due to recent data concerning potential risks and toxicities, the use of erythropoietin-stimulating agents should be utilized only when necessary.

f) How should hypertension induced by TKI therapy be managed?

Hypertension is a class effect of VEGF/VEGFR inhibitors, and can be seen in 30-50% of patients receiving these agents. Hypertension is therefore commonly observed event during treatment, and is generally manageable with use of standard antihypertensive agents. An interesting association between hypertension and clinical efficacy appears to exist with TKI therapy.

In a retrospective analysis the occurrence of hypertension was associated with increased PFS and survival. This data suggests that in patients with mRCC, hypertension may not only be an adverse event, but also a potential prognostic biomarker. Pre-existing hypertension is not a contraindication to therapy, and worsening hypertension (grade 3) generally should be manageable with a change in antihypertensive medications, with dose reductions or interruption reserved for uncontrolled elevations of blood pressure.

g) How should pneumonitis secondary to administration of mTOR inhibitors be managed?

Non-infectious pneumonitis is a potentially serious adverse event associated with rapamycin and rapamycin derivative therapy. Clinically, it can present as a typical radiographic appearance of interstitial pneumonitis with or without signs and symptoms (pleural effusion, hypoxia, cough, dyspnea, malaise). It is defined as the radiographic lung change irrespective of signs or symptoms, in the absence of a non-drug cause.

Administration of both everolimus and temsirolimus has been reported to produce pulmonary toxicity. In the RECORD 1 trial, 8% of patients receiving everolimus developed pneumonitis, and 8 (3%) were grade 3. Of the 8 patients with grade 3 pneumonitis, six discontinued everolimus, four resolved completely, and three improved to grade 2 or less.

Recommendations for management depend upon the severity of the pneumonitis. Patients should be instructed to report any new or changing respiratory symptoms. In asymptomatic patients, with radiographic changes only, everolimus can be continued, and patients observed closely.

In patients with moderate symptoms, therapy should be held, and restarted when symptoms improve with a dose reduction of everolimus to 5mg daily. In patients with severe pneumonitis (grade 3), everolimus should be discontinued. The role of corticosteroids in improving the interstitial pneumonitis is unclear, but they can be utilized in this group.

The development of pneumonitis secondary to temsirolimus was investigated retrospectively in the phase 3 pivotal trial (ARCC) utilizing blinded radiology review. 29% of the evaluable patients receiving temsirolimus developed radiographic evidence of drug-related pneumonitis, compared to 6% of patient receiving IFN-a.

In contrast, the investigators reported the incidence of temsirolimus-related pneumonitis as 2%. 16/52 patients with pneumonitis developed symptoms (31%), which developed during the first 8 weeks of therapy in 60% of patients. Patients with radiographic changes of pneumonitis who are asymptomatic should continue treatment and be monitored closely for respiratory symptoms. Patients who develop symptoms and radiographic changes should have treatment held. Treatment with temsirolimus may be resumed, with or without dose reduction (15mg weekly), depending on the patient’s clinical course.

An important concept in the evaluation of the pneumonitis related to mTOR inhibitors involves further assessment with pulmonary function tests and bronchoscopy to exclude other causes, e.g. infection. Empiric therapy with corticosteroids and antibiotics may be initiated if clinically warranted. Continuation of these agents in patients who are benefiting from treatment involves the availability of other treatment options, and the overall risk/benefit assessment.

Clinical syndromes include pneumonitis, thyroiditis, colitis, hepatitis, dermatitis, nephritis, hypophysitis, endophthalmitis have been reported. Frequency of events varies by agent and class, although generally the incidence of grade 3-4 autoimmune toxicities is less than 5%.

Depending on the severity of the toxicity, treatment is either withheld or permanently discontinued. There are no dose reductions. The mainstay of management is corticosteroids. A typical approach might be prednisone 1 mg/kg equivalent daily. Once toxicity has improved to grade 1 in severity, a 4-6 week taper is initiated. Oral budesonide has also been used for treatment of colitis. Only if symptoms remain improved after taper completion is the immunotherapeutic agent re-initiated. In some instances, other immune-modulating agents such as TNF inhibitors may be warranted. Consultation with appropriate medical services (endocrinology, pulmonary medicine, gastroenterology, nephrology) for assistance with diagnosis and treatment may be considered. For patients with treatment-related hypothyroidism and adrenal insufficiency, replacement with levothyroxine and hydrocortisone is given.

Follow-up surveillance and therapy/management of recurrences.

Recommendations for follow-up and surveillance will vary depending upon the stage, type of surveillance and whether active therapy is ongoing. These individual situations are discussed in the following paragraphs.

These recommendations are based on the NCCN treatment guidelines for localized RCC. The possibility that more prolonged observation for selected patients should be considered has been suggested.

Patients with small renal mass (<4.0 cm) being considered for active surveillance

In this setting determination of the characteristics of the renal mass and the growth rate are important. No accepted guidelines exist; however, the NCCN guidelines for follow-up of patients following therapy for a localized renal tumor are applicable. These can be individualized depending upon the patient and tumor characteristics.

Patients with metastatic renal cell carcinoma

a) Receiving systemic therapy including TKIs, mTOR inhibitors, and bevacizumab plus IFN-a. Standardized guidelines do not exist, however, the following should be considered during active therapy, until disease progression.

Every 4 to 6 weeks, dependent upon type of therapy and treatment schedule:

Radionuclide LVEF if at baseline this was abnormal, or the patient has a history of cardiovascular disease.

Annually: CT scan or MRI of brain

These recommendations will vary depending upon the patient, type of tumor, and type of systemic therapy. The guidelines for follow-up of patients with metastatic RCC reflect the type of follow-up obtained during the clinical trials of the approved agents for treating RCC, as well as the natural history of mRCC.

b) Patients with metastatic RCC, under observation and not receiving active therapy. The recommendations reflect the underlying metastatic RCC, no standard accepted guidelines are available.

Every 3 months:

History and physical examination.

CT scans: chest, abdomen, pelvis.

Complete blood count, metabolic profile.

Annually:

CT or MRI of brain.

Bone scan.

Pathophysiology

The molecular characteristics of RCC have been intensively studied during the past 20 years. Approximately 2 to 3% of RCC tumors are familial. Several autosomal dominant syndromes have now been described, each having a distinct genetic basis and phenotype. The von Hippel-Lindau (VHL) syndrome is the most common.

These patients develop vascular tumors including clear cell RCC, hemangioblastomas, and pheochromocytomas. The VHL tumor suppressor gene is located on chromosome 3 (3p25-26). In patients with the VHL syndrome, a defect on one VHL gene allele is inherited, and a second in the remaining allele is then acquired.

Studies in the 1990s demonstrated most patients (>80%) with sporadic clear cell RCC acquire defects of both VHL gene alleles, producing dysfunction of the VHL protein. This functions as a tumor suppressor, and is responsible for proteasome degradation of hypoxia-inducible factor (HIF), a regulator of the hypoxic response. When VHL protein is absent or non-functioning, HIF-1-alpha accumulates, and activates transcription of hypoxia-inducible genes, such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF).

Clear cell cancers are characterized by high vascular content, secondary to enhanced tumor associated angiogenesis. The loss of VHL gene function results in constitutive expression of HIF, over secretion of VEGF, PDGF, and produces the vascular phenotype characteristic of clear cell RCC.

Cytogenetics and gene expression profiling studies have also clarified the molecular characteristics of RCC non-clear cell histologic subtypes. Morphologically, papillary RCC is divided into type 1 and type 2, but genetic patterns in the inherited papillary RCC syndromes may also differentiate the two. Chromophobe carcinomas and oncytomas are uncommon non-clear cell variants. Chromophobe tumors may present as extremely large abdominal masses, are generally locally advanced tumors, and are slow growing. Oncocytomas are generally considered benign tumors, grow very slowly, and may be multifocal.

Collecting duct carcinomas (CDC) and medullary cancers of the kidney are related to transitional cell carcinomas, based on histology and gene expression profiles. They arise in the collecting ducts and medullary systems of the kidney. Collecting duct carcinoma, also referred to as “Bellini duct carcinoma,” is an uncommon, aggressive form of RCC, and accounts for less than 2% of renal tumors. It arises from the epithelium of the distal collecting system in the renal medullary pyramids. CDC is associated with a poor prognosis in patients with advanced disease.

Renal medullary carcinoma (RMC) is also a rare tumor which typically affects younger individuals with sickle cell disease or trait. It is a highly aggressive malignancy and most often produces locally advanced and metastatic disease at diagnosis. Increased levels of topoisomerase II have been recently described along with deregulation of DNA remodeling and repair. As with CDC, this RCC variant resembles more the patterns described in urothelial rather than epithelial cancers.

Translocation carcinomas of the kidney, which were first described in children, were considered as aggressive tumors. These Xp11.2 translocations RCC now constitute a well-recognized entity. In children, these tumors comprise at least one third of RCC tumors reported, but in adults, they remain a rare entity. In view of the fact these tumors overlap morphologically with clear cell and/or papillary RCC, many adult Xp11.2 translocation RCC may be misclassified as clear cell or papillary RCC.

The histologic variant of high-grade RCC referred to as sarcomatoid carcinoma refers to the spindled morphology of a dedifferentiated subset of RCC tumor cells. Approximately 4% of RCC tumors will have a sarcomatoid component. Renal cell carcinoma with sarcomatoid features is a variant of other RCC subtypes, not a separate entity. At present, the diagnosis rests on demonstration of conventional histopathologic features, assessment of the percentage of sarcomatoid dedifferentiation, and immunohistochemical stains confirming epithelial rather than mesenchymal lineage.

Finally, the category of unclassified RCC is utilized for tumors that cannot be placed in one of the previous histologic subtypes. Unclassified RCC represents a category assigned when a tumor does not fit into the other RCC histological subtypes, based on pathological and/or genetic analyses. It is a rare variant and accounts for 3–5% of RCC cases. A recent study indicated that unclassified RCC presents with a higher stage and grade, and has a higher mortality than clear cell carcinoma.

What other clinical manifestations may help me to diagnose renal cell carcinoma?

The majority of renal tumors are now discovered incidentally during an imaging procedure, and patients are asymptomatic. The classic presentation that included the triad of hematuria, flank pain and a palpable mass are seldom seen currently.

Past medical history and smoking history are important, as well as a work and environmental exposure history. Patients with suspected RCC should be examined carefully to document any evidence of metastatic or advanced disease. This includes a careful system review focusing on the skeletal, genitourinary and systemic systems.

In young patients (<40 years) with RCC, a family history is relevant, and any manifestations of the various inherited RCC syndromes should be determined.

What other additional laboratory studies may be ordered?

In patients with advanced or metastatic RCC, routine hematologic and biochemical studies are recommended. Hemoglobin levels, calcium and serum albumin, and serum LDH should be obtained to allow MSKCC classification of the untreated newly diagnosed RCC patient. There are no biomarkers or other specialized laboratory studies that are helpful during the initial evaluation. In the future, SNP analyses and tumor genetic studies may be helpful in this regard.